Pelizaeus-Merzbacher
disease (PMD) is a rare X-linked leukodystrophy disorder caused by mutations in
proteolipid protein 1 (PLP1). These mutations disrupt the
ability of oligodendrocytes to myelinate axons, which leads to neurological
deficits and eventually degeneration.

In
2010, a University of California, Irvine team reported that
human neural stem cells differentiated into mature oligodendrocytes and neurons
and helped restore locomotor function in rodents with spinal cord injury.3

Building on that work, researchers from OHSU and StemCells
decided to test whether these cells could differentiate into myelin-
producing oligodendrocytes to help treat myelination disorders.

The
group transplanted human fetal neural stem cells into an immunodeficient mouse
model of hypomyelination. The neonatal mice given the transplant showed
widespread engraftment of the human cells, which differentiated into
myelin-producing oligodendrocytes in appropriate brain regions and produced
myelin sheaths on axons.

The
team repeated the procedure in juvenile mice with extensive demyelination and
found similar increases in myelinated neurons, suggesting the strategy could
indeed replace lost myelin.

In
tissue samples from both the juvenile and neonatal mouse brains, action
potentials had higher amplitude in mice treated with neural stem cells than
those in vehicle-treated or human liver mesenchymal stem cell-treated controls.

Based
on these mouse data, StemCells sponsored a Phase I, open-label trial of the
technique in four patients with early severe PMD. The trial was run by David
Rowitch, professor of pediatrics and neurological surgery at UCSF and a Howard Hughes Medical Institute investigator, and
Nalin Gupta, associate professor of neurological surgery and pediatrics and
chief of pediatric neurological surgery at UCSF Benioff Children's Hospital.

At
12 months post-transplant, all patients were stable or had modest gains in
motor function. Patients also had minor gains in cognitive function.

Diffusion MRI, which maps the diffusion of water molecules
to determine the composition of tissues, suggested the presence of myelin in
the patients. None of the patients had detectable myelin before surgery.

The
human and mouse studies were published as separate papers in the same issue of Science
Translational Medicine.

According
to Gupta, "In general, patients with severe forms of PMD demonstrate a
progressively worsening clinical course. The changes we observed in some of the
transplanted children amounted to better motor function and improvement in developmental
milestones."

Future
trials

The patients from the Phase I trial are being studied by the
UCSF team in a four-year follow-up.

"We
will be looking primarily for any adverse effects of the cells in the follow-up
study, but we will also be monitoring MRI and clinical outcomes," said
Rowitch. "We are interested to see how the story continues to evolve and
see if the signs that the cells have engrafted and are producing myelin
continue to become more obvious with time."

"They
do need to determine if the cells are safe in the long term. Tumorigenesis has
been caused by neural stem cells in isolated examples," said Spyros
Deftereos, VP of drug discovery at Biovista Inc.

Biovista
has BVA-101 and the BVA-20x class of compounds
with undisclosed mechanisms in preclinical testing to treat multiple sclerosis
(MS). The company did not disclose further details.

"Tumors
are a risk that we are watching out for," acknowledged Rowitch. "Because
this is such an early generation trial, we can't be exactly sure what the
potential adverse effects of the cells will be. In the first year of the study,
we have had a very favorable safety profile."

Gresser
told SciBX, "In order for the recipient to receive these donor
cells, the patient will have to be treated with immune-suppressing drugs to
keep their immune systems from rejecting the donated cells, just as organ transplant
recipients have to be treated with immune-suppressing drugs. Immune suppression
carries the risk of infections and adverse effects."

"Researchers
need to understand for how long and at what level immunosuppression would be
required for this type of treatment to have meaningful, long-term benefit,"
said Mays. Athersys is developing MultiStem, a multipotent
adult progenitor cell-based approach to reduce neuroinflammation associated
with CNS injuries and disease. MultiStem cells are in preclinical testing to
treat MS and in clinical trials to treat ischemic stroke.

Rowitch
told SciBX that his team has not seen any changes in immune reaction
toward the transplanted cells after ceasing immunosuppressive therapy.

"We noted persistence of the MRI signals after
discontinuing immunosuppression. In future studies, it will be important to
carefully monitor and manage the potential for cell rejection by the patient,"
he said.

Deftereos
suggested that a solution to the issue of immunogenicity would be to use
autologous stem cells. "The technology exists to dedifferentiate a patient's
cells into pluripotent cells, then redifferentiate them into neural stem cells,"
he said.

Jason
Hamilton, senior scientist at Athersys, said autologous cells could be a
solution to myelination disorders that are not known to be caused by a genetic
mutation, such as MS. However, he said, autologous stem cells isolated from
patients with PMD or other genetic myelination disorders will have the same
mutations as the dysfunctional, myelin-producing cells causing the disease,
which may limit their effectiveness as a treatment option.

Other
myelination disorders

In parallel with the Phase I extension study, StemCells is
planning a Phase II trial.

In
addition to the program in PMD, StemCells thinks the transplantation strategy
could extend to other neurological disorders, "including certain cerebral
palsies, transverse myelitis and even spinal cord injury in certain cases,"
said Stephen Huhn, VP and head of the CNS program at StemCells.

He
added, "MS is another potential indication. The issue is that it will
require unique clinical considerations. MS is an autoimmune disease, and cell
therapy could play a role in MS, but it would also be necessary to control the
autoimmunity."

Indeed,
MRF's Gresser was skeptical about the potential for the cell-based approach in
MS.

"MS
is not associated with a known genetic mutation that may impair their ability
to myelinate axons. Due to this lack of genetic variation, we feel that this
strategy will most likely not be applicable for MS patients but instead could
be beneficial for patients with a genetic disorder such as PMD," he said.

Hamilton
added, "In the case of an autoimmune disease like MS, in which the
demyelination is caused by a systemic autoimmune reaction, this type of
cell-based approach would be limited if you don't use an adjunctive therapy to
address the autoimmune component. There would be no way to stop the body from
attacking the production of new myelin by the transplanted cells."

"There could be synergy between the approaches
described in these papers and strategies that modulate the negative effects of
neuroinflammation. For example, treatment with MultiStem cells may slow or stop
neuroinflammation and thereby give subsequently transplanted neural stem cells
the chance to engraft and make myelin in a less hostile environment. We are
excited about the idea of this synergistic potential," added Mays.

Huhn
told SciBX that StemCells holds patents related to both the human and
mouse studies. The IP is available for licensing.

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